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長谷 善明
医学部附属病院 腫瘍・血液内科
助教

研究者基本情報

■ 学位
  • 博士（医学）, 神戸大学
■ 研究キーワード
  • 消化器がん
■ 研究分野
  • ライフサイエンス / 免疫学
  • ライフサイエンス / 血液、腫瘍内科学

研究活動情報

■ 論文
  • T. Koyama, N. Kiyota, S. Boku, Y. Imamura, N. Shibata, H. Satake, K. Tanaka, H. Hayashi, T. Onoe, Y. Asada, T. Yamazaki, T. Nose, S. Ohata, Y. Nagatani, S. Kimbara, Y. Funakoshi, M. Teshima, H. Shinomiya, H. Minami
    2024年08月, ESMO Open, 9(8) (8)
    研究論文（学術雑誌）

  • Yohei Funakoshi, Kimikazu Yakushijin, Goh Ohji, Takaji Matsutani, Kazuhiko Doi, Hironori Sakai, Tomoki Sasaki, Takahiro Kusakabe, Sakuya Matsumoto, Yasuyuki Saito, Shinichiro Kawamoto, Katsuya Yamamoto, Taiji Koyama, Yoshiaki Nagatani, Keiji Kurata, Shiro Kimbara, Yoshinori Imamura, Naomi Kiyota, Mitsuhiro Ito, Hironobu Minami
    Monovalent Omicron XBB.1.5 mRNA vaccines were newly developed and approved by the FDA in Autumn 2023 for preventing COVID-19. However, clinical efficacy for these vaccines is currently lacking. We previously established the quantification of antigen-specific antibody sequence (QASAS) method to assess the response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination at the mRNA level using B-cell receptor (BCR) repertoire assay and the coronavirus antibody database (CoV-AbDab). Here, we used this method to evaluate the immunogenicity of monovalent XBB.1.5 vaccines. We analyzed repeated blood samples of healthy volunteers before and after monovalent XBB.1.5 vaccination (BNT162b2 XBB.1.5 or mRNA-1273.815) for the BCR repertoire to assess BCR/antibody sequences that matched SARS-CoV-2-specific sequences in the database. The number of matched unique sequences and their total reads quickly increased 1 week after vaccination. Matched sequences included those bound to the Omicron strain and Omicron XBB sublineage. The antibody sequences that can bind to the Omicron strain and XBB sublineage revealed that the monovalent XBB.1.5 vaccines showed a stronger response than previous vaccines or SARS-CoV-2 infection before the emergence of XBB sublineage. The QASAS method was able to demonstrate the immunogenic effect of monovalent XBB.1.5 vaccines for the 2023-2024 COVID-19 vaccination campaign.
    2024年08月, EJHaem, 5(4) (4), 661 - 668, 英語, 国際誌
    研究論文（学術雑誌）

  • T. Koyama, N. Kiyota, S. Boku, Y. Imamura, N. Shibata, H. Satake, K. Tanaka, H. Hayashi, T. Onoe, Y. Asada, T. Yamazaki, T. Nose, S. Ohata, Y. Nagatani, S. Kimbara, Y. Funakoshi, M. Teshima, H. Shinomiya, H. Minami
    2024年06月, ESMO Open, 9(6) (6)
    研究論文（学術雑誌）

  • Hironobu Goto, Taro Oshikiri, Takashi Kato, Yoshiaki Nagatani, Yohei Funakoshi, Yasufumi Koterazawa, Ryuichiro Sawada, Hitoshi Harada, Naoki Urakawa, Hiroshi Hasegawa, Shingo Kanaji, Kimihiro Yamashita, Takeru Matsuda, Hironobu Minami, Yoshihiro Kakeji
    BACKGROUND: In Japan, preoperative adjuvant chemotherapy followed by surgical resection is the standard treatment for patients with locally advanced esophageal squamous cell carcinoma. However, the risk of recurrence after surgical resection remains high. Although a randomized controlled trial evaluating the efficacy of nivolumab, a fully human monoclonal anti-programmed death 1 antibody, as postoperative adjuvant therapy after neoadjuvant chemoradiotherapy and surgery established its superior efficacy as adjuvant therapy, the efficacy for patients who received preoperative adjuvant chemotherapy has not been demonstrated. This study aims to elucidate the efficacy and safety of nivolumab as postoperative adjuvant therapy for patients with esophageal squamous cell carcinoma after preoperative adjuvant chemotherapy with docetaxel and cisplatin plus 5-fluorouracil followed by surgical resection. METHODS: This study is a multi-institutional, single-arm, Phase II trial. We plan to recruit 130 esophageal squamous cell carcinoma patients, who have undergone preoperative adjuvant chemotherapy with docetaxel and cisplatin plus 5-fluorouracil followed by surgical resection. If the patient did not have a pathological complete response, nivolumab is started as a postoperative adjuvant therapy within 4-16 weeks after surgery. The nivolumab dose is 480 mg/day every four weeks. Nivolumab is administered for up to 12 months. The primary endpoint is disease-free survival; the secondary endpoints are overall survival, distant metastasis-free survival, and incidence of adverse events. DISCUSSION: To our knowledge this study is the first trial establishing the efficacy of nivolumab as postoperative adjuvant therapy for patients with esophageal squamous cell carcinoma after preoperative adjuvant chemotherapy with docetaxel and cisplatin plus 5-fluorouracil followed by surgical resection. In Japan, preoperative adjuvant chemotherapy followed by surgery is a well-established standard treatment for resectable, locally advanced esophageal squamous cell carcinoma. Therefore, developing an effective postoperative adjuvant therapy has been essential for improving oncological outcomes.
    2024年, PloS one, 19(4) (4), e0299742, 英語, 国際誌
    研究論文（学術雑誌）

  • Shun Yamamoto, Ken Kato, Hiroyuki Daiko, Yoshinori Ito, Takeshi Kajiwara, Takashi Kojima, Hiroshi Miyata, Satoru Nakagawa, Masaki Ueno, Masaya Watanabe, Shigeru Tsunoda, Tetsuya Abe, Yoshiaki Nagatani, Morihito Okada, Masaru Morita, Takuji Sato, Junki Mizusawa, Kenichi Nakamura, Yuko Kitagawa
    Aim: Treatment options for esophageal squamous cell carcinoma includes surgery and chemoradiotherapy (CRT), however there was limited information about the factors influenced in patients' decision-making.Materials & methods: Patients who participated in JCOG0502, a parallel group controlled trial comparing surgery with CRT, were analyzed for the factors related to decision-making.Results: Of the 368 patients (pts) enrolled in the nonrandomized part in JCOG0502, 209 pts opted for surgery and 159 pts chose CRT on their own. Background characteristics were the same except for age. Multivariable logistic regression analysis showed that age ≥65 years, male sex, multiple lesions, absence of children and doctor's thinking were associated with the selection of CRT.Conclusion: The doctor's option was the most influential factor in the patient's decision-making process.Clinical Trial Registration: UMIN000000551 (ClinicalTrials.gov).
    2024年, Future oncology (London, England), 20(36) (36), 2849 - 2854, 英語, 国際誌
    研究論文（学術雑誌）

  • Goh Ohji, Yohei Funakoshi, Kimikazu Yakushijin, Takaji Matsutani, Tomoki Sasaki, Takahiro Kusakabe, Sakuya Matsumoto, Taiji Koyama, Yoshiaki Nagatani, Keiji Kurata, Shiro Kimbara, Naomi Kiyota, Hironobu Minami
    A monovalent Omicron XBB.1.5 mRNA RBD analogue vaccine, MAFB-7256a (DS-5670d), was newly developed and approved in Japan in the Spring of 2024 for the prevention of COVID-19. However, clinical efficacy data for this vaccine are currently lacking. We previously established the Quantification of Antigen-specific Antibody Sequence (QASAS) method to assess the response to SARS-CoV-2 vaccination at the mRNA level using B-cell receptor (BCR) repertoire assays and the Coronavirus Antibody Database (CoV-AbDab). Here, we used this method to evaluate the immunogenicity of MAFB-7256a. We analyzed repeated blood samples using the QASAS method from three healthy volunteers before and after MAFB-7256a vaccination. BCR response increased rapidly one week post-vaccination and then decreased, as with conventional vaccine. Notably, the matched sequences after MAFB-7256a vaccination specifically bound to the receptor-binding domain (RBD), with no sequences binding to other epitopes. These results validate that MAFB-7256a is an effective vaccine that exclusively induces antibodies specific for the RBD, demonstrating its targeted immunogenic effect.
    2024年, Frontiers in immunology, 15, 1468760 - 1468760, 英語, 国際誌
    研究論文（学術雑誌）
    神戸大学リポジトリ（Kernel）へのリンク

  • Yohei Funakoshi, Kimikazu Yakushijin, Goh Ohji, Takaji Matsutani, Wataru Hojo, Hironori Sakai, Sakuya Matsumoto, Marika Watanabe, Akihito Kitao, Yasuyuki Saito, Shinichiro Kawamoto, Katsuya Yamamoto, Taiji Koyama, Yoshiaki Nagatani, Shiro Kimbara, Yoshinori Imamura, Naomi Kiyota, Mitsuhiro Ito, Hironobu Minami
    The use of anti-SARS-CoV-2 antibody products like tixagevimab/cilgavimab represents an important strategy to protect immunocompromised patients with haematological malignancies from COVID-19. Although patients who receive these agents should still be vaccinated, the use of tixagevimab/cilgavimab can mask the production of anti-spike antibody after vaccination, making it hard to assess vaccine response. We have newly established a quantification method to assess the response to SARS-CoV-2 vaccination at the mRNA level using B-cell receptor (BCR) repertoire assay and the Coronavirus Antibody Database (CoV-AbDab). Repeated blood samples before and after vaccination were analysed for the BCR repertoire, and BCR sequences were searched in the database. We analysed the number and percentage frequency of matched sequences. We found that the number of matched sequences increased 2 weeks after the first vaccination and quickly decreased. Meanwhile, the number of matched sequences more rapidly increased after the second vaccination. These results show that the postvaccine immune response can be assessed at the mRNA level by analysing the fluctuation in matching sequences. Finally, BCR repertoire analysis with CoV-AbDab clearly demonstrated the response to mRNA SARS-CoV-2 vaccination even after tixagevimab/cilgavimab administration in haematological malignancy patients who underwent allogeneic haematopoietic stem cell transplantation.
    Wiley, 2023年08月, British Journal of Haematology, 202(3) (3), 504 - 516, 英語, 国際誌
    研究論文（学術雑誌）

  • Yoshiaki Nagatani, Naomi Kiyota, Yoshinori Imamura, Taiji Koyama, Yohei Funakoshi, Masato Komatsu, Tomoo Itoh, Masanori Teshima, Ken-Ichi Nibu, Kazuko Sakai, Kazuto Nishio, Manami Shimomura, Tetsuya Nakatsura, Daiki Ikarashi, Takayuki Nakayama, Shigehisa Kitano, Hironobu Minami
    AIM: Although immune checkpoint inhibitors (ICPi) for salivary gland cancer (SGC) have been investigated in clinical trials, details of the tumor immune microenvironment (TIME) remain unclear. This research aimed to elucidate the TIME of SGC and its relationship with tumor mutation burden (TMB) and to explore the rationale for the applicability of ICPi. MATERIALS AND METHODS: We selected five pathological types, namely adenoid cystic carcinoma (ACC); adenocarcinoma, not otherwise specified (ANOS); salivary duct carcinoma (SDC); and low/high-grade mucoepidermoid carcinoma (MEClow/high). We investigated the TIME and TMB of each pathological type. TIME was evaluated by multiplexed fluorescent immunohistochemistry. TMB was measured by next-generation sequencing. RESULTS: ACC and MEChigh showed the lowest and highest infiltration of immune effector and suppressor cells in both tumor and stroma. ANOS, SDC, and MEClow showed modest infiltration of immune effector cells in tumors. Correlation analysis showed a positive correlation between CD3+CD8+ T cells in tumor and TMB (r = 0.647). CD3+CD8+ T cells in tumors showed a positive correlation with programmed cell death-ligand 1 expression in tumor cells (r = 0.513) and a weak positive correlation with CD3+CD4+Foxp3+ cells in tumors (r = 0.399). However, no correlation was observed between CD3+CD8+ T cells and CD204+ cells in tumors (r = -0.049). CONCLUSION: The TIME of ACC was the so-called immune desert type, which may explain the mechanisms of the poor response to ICPi in previous clinical trials. On the other hand, MEChigh was the immune-inflamed type, and this may support the rationale of ICPi for this pathological subtype.
    2023年07月, Asia-Pacific journal of clinical oncology, 20(6) (6), 779 - 788, 英語, 国際誌
    [査読有り]
    研究論文（学術雑誌）

  • Yuhi Shimura, Shohei Komatsu, Yoshiaki Nagatani, Yohei Funakoshi, Keitaro Sofue, Masahiro Kido, Kaori Kuramitsu, Hidetoshi Gon, Kenji Fukushima, Takeshi Urade, Shinichi So, Hiroaki Yanagimoto, Hirochika Toyama, Hironobu Minami, Takumi Fukumoto
    BACKGROUND: Few reports have discussed the association between total tumor volume (TTV) and prognosis in patients with colorectal liver metastases (CRLM). The present study aimed to evaluate the usefulness of TTV for predicting recurrence-free survival and overall survival (OS) in patients receiving initial hepatic resection or chemotherapy, and to investigate the value of TTV as an indicator for optimal treatment selection for patients with CRLM. PATIENTS AND METHODS: This retrospective cohort study included patients with CRLM who underwent hepatic resection (n = 93) or chemotherapy (n = 78) at the Kobe University Hospital. TTV was measured using 3D construction software and computed tomography images. RESULTS: A TTV of 100 cm3 has been previously reported as a significant cut-off value for predicting OS of CRLM patients receiving initial hepatic resection. For patients receiving hepatic resection, the OS for those with a TTV ≥ 100 cm3 was significantly reduced compared with those with a TTV < 100 cm3. For patients receiving initial chemotherapy, there were no significant differences between the groups divided according to TTV cut-offs. Regarding OS of patients with TTV ≥ 100 cm3, there was no significant difference between hepatic resection and chemotherapy (p = 0.160). CONCLUSIONS: TTV can be a predictive factor of OS for hepatic resection, unlike for initial chemotherapy treatment. The lack of significant difference in OS for CRLM patients with TTV ≥ 100 cm3, regardless of initial treatment, suggests that chemotherapeutic intervention preceding hepatic resection may be indicated for such patients.
    Springer Science and Business Media {LLC}, 2023年06月, Annals of Surgical Oncology, 30(11) (11), 6603 - 6610, 英語, 国際誌
    研究論文（学術雑誌）

  • Taku Nose, Yohei Funakoshi, Hirotaka Suto, Yoshiaki Nagatani, Yoshinori Imamura, Masanori Toyoda, Naomi Kiyota, Hironobu Minami
    Although nivolumab is administered every two or four weeks, high programmed cell death-1 (PD-1) binding of nivolumab on T cells lasting for several months has been reported. A relationship between the PD-1 occupancy rate on T-cells and the efficacy of nivolumab is not yet fully understood. The present study used flow cytometric analyses to determine the time-dependence of PD-1 occupancy in five patients who discontinued nivolumab. The relationship between PD-1 occupancy at relapse and the efficacy of re-challenge was also studied. Occupancies after discontinuation were measured at a total of 32 points. The data indicated that it took 32.4 and 48.9 weeks to decrease occupancy by 50 and 70%, respectively. Subsequently, two patients had recurrence and were re-challenged with nivolumab. At that time, one patient had 70.8% occupancy while the other had 6.6%. Treatment was effective only for the patient with lower occupancy. Overall, the present study suggests that re-challenge with nivolumab may be efficacious in patients with low occupancy at recurrence.
    Spandidos Publications, 2022年04月, Molecular and Clinical Oncology, 16(5) (5), 104 - 104, 英語, 国際誌
    研究論文（学術雑誌）

  • Yohei Funakoshi, Kimikazu Yakushijin, Goh Ohji, Wataru Hojo, Hironori Sakai, Ryo Takai, Taku Nose, Shinya Ohata, Yoshiaki Nagatani, Taiji Koyama, Akihito Kitao, Meiko Nishimura, Yoshinori Imamura, Kiyota N, Kenichi Harada, Yugo Tanaka, Yasuko Mori, Hironobu Minami
    BACKGROUND: Although COVID-19 severity in cancer patients is high, the safety and immunogenicity of the BNT162b2 mRNA COVID-19 vaccine in patients undergoing chemotherapy for solid cancers in Japan have not been reported. METHODS: We investigated the safety and immunogenicity of BNT162b2 in 41 patients undergoing chemotherapy for solid cancers and in healthy volunteers who received 2 doses of BNT162b2. We evaluated serum IgG antibody titers for S1 protein by ELISA at pre-vaccination, prior to the second dose and 14 days after the second vaccination in 24 cancer patients undergoing cytotoxic chemotherapy (CC group), 17 cancer patients undergoing immune checkpoint inhibitor therapy (ICI group) and 12 age-matched healthy volunteers (HV group). Additionally, inflammatory cytokine levels were compared between the HV and ICI groups at pre and the next day of each vaccination. RESULTS: Anti-S1 antibody levels were significantly lower in the ICI and CC groups than in the HV group after the second dose (median optimal density: 0.241 [0.063-1.205] and 0.161 [0.07-0.857] vs 0.644 [0.259-1.498], p = 0.0024 and p < 0.0001, respectively). Adverse effect profile did not differ among the three groups, and no serious adverse event occurred. There were no differences in vaccine-induced inflammatory cytokines between the HV and ICI groups. CONCLUSION: Although there were no significant differences in adverse events in three groups, antibody titers were significantly lower in the ICI and CC groups than in the HV group. Further protection strategies should be considered in cancer patients undergoing CC or ICI.
    Elsevier {BV}, 2022年04月, Journal of Infection and Chemotherapy, 28(4) (4), 516 - 520, 英語, 国際誌
    研究論文（学術雑誌）

  • AOI OKAMOTO, YOHEI FUNAKOSHI, MASAHIRO OE, RYO TAKAI, HIROTAKA SUTO, YOSHIAKI NAGATANI, MEIKO NISHIMURA, YOSHINORI IMAMURA, TOMONARI KUNIHISA, NAOMI KIYOTA, KOJI MIKI, KOUICHI OHE, HIROKAZU TANINO, HIRONOBU MINAMI
    BACKGROUND/AIM: Aldehyde dehydrogenase (ALDH) 1A1 is a well-known marker for cancer stem cells (CSCs), characterized by self-renewal capacity and multidrug resistance in breast cancer. We developed a near-infrared turn-on fluorescence probe for ALDH1A1, C5S-A, which is suitable for observing and analyzing viable cells. Here, we demonstrated the utility of C5S-A in CSC research using breast cancer cell lines. MATERIALS AND METHODS: To evaluate concordance between C5S-A and conventional stem cell markers, breast cancer cells sorted for ALDEFLUOR-positive cells and for CD44+/CD24- cell populations were stained with C5S-A. Tumorigenicity of C5S-A-positive cells was examined by mammosphere formation assay and subcutaneous transplantation to immunodeficient mice. Additionally, to determine how long fluorescence from a single staining remained observable, we cultured breast cancer cells for 5 days after C5S-A staining. We then evaluated whether C5S-A-positive cells possessed resistance to cytotoxic drugs by chronological imaging. RESULTS: C5S-A staining showed good concordance with conventional breast CSC markers, and good utility for research into CSC characteristics in breast cancer cell lines, including tumorigenesis. Additionally, C5S-A was observable for more than 3 days with a single staining. Using this property, we then confirmed that C5S-A-positive cells possessed resistance to cytotoxic drugs, which is one of the characteristics of CSCs. CONCLUSION: We showed that C5S-A is suitable for CSC research using breast cancer cell lines, and confirmed its utility in observing cells over time.
    Anticancer Research {USA} Inc., 2022年03月, Anticancer Research, 42(3) (3), 1199 - 1205, 英語, 国際誌
    研究論文（学術雑誌）

  • Yoshinori Imamura, Kaoru Tanaka, Kiyota N, Hidetoshi Hayashi, Ichiro Ota, Akihito Arai, Shigemichi Iwae, Shujiro Minami, Katsunari Yane, Tomoko Yamazaki, Yoshiaki Nagatani, Masanori Toyoda, Takayuki Takahama, Kazuko Sakai, Kazuto Nishio, Naoki Otsuki, Ken-ichi Nibu, Hironobu Minami
    The clinical utility of systemic therapy and genomic profiling in non-squamous-cell head and neck cancer (NSCHNC) has not been fully elucidated. This phase II trial evaluated the efficacy and safety of docetaxel and cisplatin combination in the first-line setting. Eligibility criteria were recurrent and/or metastatic NSCHNC; progressive disease within the last 6 months; no prior systemic therapy; and ECOG performance status of 0-1. Patients received docetaxel (75 mg/m2 on day 1) and cisplatin (75 mg/m2 on day 1), repeated every 21 days for 6 cycles. The primary endpoint was confirmed objective response rate (ORR). The secondary endpoints included progression-free survival (PFS), overall survival (OS), and adverse events. Next-generation sequencing (NGS) was performed using the Ion AmpliSeq Cancer Hotspot Panel v2. Twenty-three patients were enrolled from November 2012 to October 2016, of whom 8 were male. Median age was 57 years. Ninety-six percent of cases were metastatic. Among 22 evaluable patients, confirmed ORR was 45% (95% confidential interval 24-68%). With a median follow-up period of 18.8 months, median PFS and OS were 6.7 and 20.1 months, respectively. Grade 3/4 adverse events included febrile neutropenia (39%) and anemia (22%). No treatment-related deaths were observed. NGS analysis revealed potential treatment targets, including ERBB2, KIT, and ALK. The docetaxel and cisplatin combination regimen can be considered a new treatment option in recurrent and/or metastatic NSCHNC, although primary prophylaxis for febrile neutropenia should be considered. Diverse genomic alterations may lead novel treatment options.This trial was registered with the UMIN Clinical Trials Registry as UMIN000008333 on [September 1st, 2012].
    Springer Science and Business Media {LLC}, 2021年11月, Medical Oncology, 38(11) (11), 128 - 128, 英語, 国際誌
    研究論文（学術雑誌）

  • RYO TAKAI, YOHEI FUNAKOSHI, HIROTAKA SUTO, YOSHIAKI NAGATANI, YOSHINORI IMAMURA, MASANORI TOYODA, KIMIKAZU YAKUSHIJIN, NAOMI KIYOTA, KEN-ICHI HARADA, KIMIHIRO YAMASHITA, YOSHIHIRO KAKEJI, HIRONOBU MINAMI
    BACKGROUND/AIM: Biomarkers for immune-related adverse events (irAEs) induced by immune checkpoint inhibitors (ICIs) are required. We encountered a patient whose skin irAE fluctuated in parallel with serum soluble interleukin-2 receptor (sIL-2R). PATIENTS AND METHODS: We examined 15 patients with cancer who received ICIs. Serum sIL-2R levels before and during ICI treatment were measured. The sIL-2R levels of preserved serum samples from another five patients who developed grade 3 irAEs were measured. RESULTS: Twelve patients showed no significant changes in sIL-2R levels during ICI treatment. Baseline serum sIL-2R levels in three patients increased beyond the normal range before the second cycle. These three patients had grade ≥2 irAEs at the second cycle treatment visit, supporting our hypothesis. Furthermore, at diagnosis of irAEs, the sIL-2R levels of all preserved samples from patients with grade 3 irAEs were significantly elevated. CONCLUSION: Serum sIL-2R is a promising biomarker for the diagnosis of irAEs.
    Anticancer Research {USA} Inc., 2021年02月, Anticancer Research, 41(2) (2), 1021 - 1026, 英語, 国際誌
    研究論文（学術雑誌）

  • Yoshiaki Nagatni, Yohei Funakoshi, Hirotaka Suto, Yoshinori Imamura, Masanori Toyoda, Naomi Kiyota, Kimihiro Yamashita, Hironobu Minami
    CONTEXT: Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immune cells of myeloid lineage. Recent reports have suggested that human MDSC are divided into three subsets: monocytic MDSC (M-MDSC), granulocytic MDSC (G-MDSC), and immature MDSC (I-MDSC). However, the characteristics of each human MDSC subset still remain unclear. MATERIALS AND METHODS: To evaluate the immunosuppressive effects and mechanisms, we first performed a T-cell suppression assay using cells obtained from healthy donor peripheral blood samples. The levels of immune inhibitory molecules in the culture supernatant of each MDSC subset were measured to reveal the T-cell suppressive mechanisms. Then, we compared these results with the results from cells obtained from cancer patient blood samples. Finally, we investigated the difference in the frequency of each MDSC subset between the healthy donors and the cancer patients. RESULTS: Although M-MDSC and G-MDSC suppressed T-cell activation, I-MDSC had no T-cell suppressive effect. We found that the culture supernatant of M-MDSC and G-MDSC contained high levels of interleukin-1 receptor antagonist (IL-1RA) and arginase, respectively, in both healthy donors and cancer patients. No inhibitory molecules were detected in the culture supernatant of I-MDSC. The population of functional MDSC (M-MDSC and G-MDSC) in the total MDSC was significantly increased in cancer patients compared with that in healthy donors. CONCLUSIONS: Although M-MDSC and G-MDSC, which released IL-1RA and arginase, respectively, suppressed T-cell activation, I-MDSC did not have an immunosuppressive effect. The population of functional MDSC was increased in cancer patients compared with that in healthy donors.
    Medknow, 2021年, Journal of Cancer Research and Therapeutics, 17(4) (4), 1093 - 1093, 英語, 国際誌
    [査読有り]
    研究論文（学術雑誌）

  • Yohei Funakoshi, Hirotaka Suto, Yoshiaki Nagatani, Yoshinori Imamura, Masanori Toyoda, Naomi Kiyota, Hisayuki Matsumoto, Shinwa Tanaka, Ryo Takai, Hiroshi Hasegawa, Kimihiro Yamashita, Takeru Matsuda, Yoshihiro Kakeji, Hironobu Minami
    CONTEXT: There is an increasing demand for appropriate preclinical mice models for evaluating the efficacy of cancer immunotherapies. AIMS: Therefore, we established a humanized patient-derived xenograft (PDX) model using microsatellite instability-high (MSI-H) colorectal cancer (CRC) tissues and patient-derived peripheral blood mononuclear cells (PBMCs). SUBJECTS AND METHODS: The CRC tissues of patients scheduled for surgery were tested for MSI status, and CRC tumors were transplanted into NOD/LtSz-scid/IL-2Rg-/-(NSG) mice to establish MSI-H PDX models. PDX tumors were compared to the original patient tumors in terms of histological and genetic characteristics. To humanize the immune system of MSI-H PDX models, patient PBMCs were injected through the tail vein. RESULTS: PDX models were established from two patients with MSI-H CRC; one patient had a germline mutation in MLH1 (c.1990-2A > G), and the other patient had MLH1 promoter hypermethylation. PDX with the germline mutation was histologically similar to the patient tumor, and retained the genetic characteristics, including MSI-H, deficient mismatch repair (dMMR), and MLH1 mutation. In contrast, the histological features of the other PDX from a tumor with MLH1 promoter hypermethylation were clearly different from those of the original tumor, and MLH1 promoter hypermethylation and MSI-H/dMMR were lost in the PDX. When T cells from the same patient with MLH1 mutation were injected into the PDX through the tail vein, they were detected in the PDX tumor. CONCLUSIONS: The MSI-H tumor with an MMR mutation is suitable for MSI-H PDX model generation. The PBMC humanized MSI-H PDX has the potential to be used as an efficient model for cancer immunotherapy research.
    Medknow, 2021年, Journal of Cancer Research and Therapeutics, 17(6) (6), 1358 - 1358, 英語, 国際誌
    研究論文（学術雑誌）

  • C. Suzuki, N. Kiyota, Y. Imamura, J. Rikitake, S. Sai, T. Koyama, Y. Hyogo, Y. Nagatani, Y. Funakoshi, M. Toyoda, N. Otsuki, KI. Nibu, H. Minami
    Springer Science and Business Media {LLC}, 2020年07月, International Journal of Clinical Oncology, 25(7) (7), 1270 - 1277, 英語
    研究論文（学術雑誌）

  • Nagatani Yoshiaki, Imamura Yoshinori, Nakamura Tsutomu, Yamashita Kazuhiko, Okuno Mamoru, Yasui Hiroyuki, Hiraoka Jun, Niigata Riho, Kono Keiji, Hyogo Yasuko, Suto Hirotaka, Takenaka Kei, Funakoshi Yohei, Toyoda Masanori, Kiyota Naomi, Minami Hironobu
    {ClinMed} International Library, 2019年09月, International Journal of Oncology Research, 2(2) (2)
    [査読有り]
    研究論文（学術雑誌）

  • Hideaki Goto, Naomi Kiyota, Naoki Otsuki, Yoshinori Imamura, Naoko Chayahara, Hirotaka Suto, Yoshiaki Nagatani, Masanori Toyoda, Toru Mukohara, Ken-ichi Nibu, Toshihiko Kasahara, Yasuhiro Ito, Akihiro Miya, Mitsuyoshi Hirokawa, Akira Miyauchi, Hironobu Minami
    Sorafenib and lenvatinib showed efficacy for patients with radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC) in pivotal phase 3 clinical trials. Although the efficacy of lenvatinib in patients who received previous treatment with multi-target kinase inhibitors (m-TKIs), including sorafenib, was reported, the efficacy of sorafenib in patients who previously received lenvatinib remains unknown. A 75-year-old woman diagnosed as RAI-refractory poorly differentiated carcinoma with multiple lung metastases and started treatment with lenvatinib. She continued to receive lenvatinib but with repeated dose interruptions and reductions due to continuous proteinuria. Because of severe and persistent proteinuria as well as newly developed renal impairment, lenvatinib was suspended after two years of treatment. After the 7-month suspension, her proteinuria and renal impairment were partially improved, but her lung metastases progressed. Because she was unable to tolerate previous treatment with lenvatinib, sorafenib was started. At 7 months of treatment with sorafenib, her lung metastases shrank and she could continue sorafenib without exacerbation of proteinuria or renal impairment. This case may suggest that sorafenib does not exacerbate the proteinuria or renal impairment induced by lenvatinib, and may be an effective treatment option for RAI-refractory DTC patients who are unable to tolerate lenvatinib.
    Elsevier {BV}, 2018年12月, Auris Nasus Larynx, 45(6) (6), 1249 - 1252, 英語, 国際誌
    研究論文（学術雑誌）

  • 再発・転移の頭頸部非扁平上皮癌に対するドセタキセル シスプラチン併用療法の第II相臨床試録
    今村善宣, 清田尚臣, 田中薫, 林秀俊, 太田一郎, 平野滋, 岩江信法, 南修司郎, 家根且有, 山崎知子, 長谷善明, 豊田昌徳, 大月直樹, 丹生健一, 南博信
    (一社)日本頭頸部癌学会, 2018年05月, 頭頸部癌, 44(2号) (2号), 126 - 126, 日本語
    [査読有り]
    研究論文（学術雑誌）

  • Yoshiaki Nagatani, Kohei Shitara, Hideaki Bando, Yasutoshi Kuboki, Wataru Okamoto, Takashi Kojima, Takayuki Yoshino, Toshirou Nishida, Atushi Ohtsu, Toshihiko Doi
    BACKGROUND: The prognosis of patients with gastrointestinal stromal tumor (GIST) after the failure of standard therapies is poor with supportive care alone. Guidelines recommend clinical trials, and patients with good performance status following standard therapies are often eligible for phase I clinical trials of investigational agents; however, there are no detailed reports on the clinical outcomes of GIST patients enrolled in these trials. METHODS: We retrospectively reviewed the clinical outcomes of 21 consecutive GIST patients who were enrolled in one or more phase I clinical trials at a single center between March 2009 and November 2014. RESULTS: The median age was 57 years, and the median number of previous lines of standard chemotherapy was three. Chemotherapy before enrollment in a phase I clinical trial included imatinib, sunitinib, and regorafenib in 100, 95, and 43 % of patients, respectively. None of the patients achieved objective response. Ten patients (47.6 %) were determined to be stable according to the Response Evaluation Criteria in Solid Tumors; four of them (19.0 %) maintained their status for more than 24 weeks. Four patients achieved partial response according to the Choi criteria. No dose-limiting toxicity was observed; however, severe adverse events and grade 3 or higher toxicities were reported in one (4.8 %) and two patients (9.5 %), respectively. Although no treatment-related deaths occurred, one patient (4.8 %) died within 30 days after the last drug administration because of disease progression. The median progression-free survival was 1.9 months, and the median overall survival time has not been reached. CONCLUSIONS: Data suggested that phase I clinical trials were feasible and may provide prognostic benefits to GIST patients after standard therapies, indicating that enrollment in these studies may provide a treatment option for these patients.
    Springer Science and Business Media {LLC}, 2016年12月, BMC Cancer, 16(1) (1), 889 - 889, 英語, 国際誌
    [査読有り]
    研究論文（学術雑誌）

  • [VEGFR inhibitor (multi-target kinase inhibitors)].
    Yoshiaki Nagatani, Toshihiko Doi
    2015年02月, Nihon rinsho. Japanese journal of clinical medicine, 73 Suppl 2, 261 - 6, 日本語, 国内誌
    研究論文（学術雑誌）

  • Hiroshi Yamashita, Kiyoshi Ashida, Takumi Fukuchi, Yoshiaki Nagatani, Hideaki Koga, Kasane Senda, Takaaki Eguchi, Satoshi Ubukata, Shinpei Kawaguchi, Aya Ueda, Toshio Tanaka, Rina Ohashi, Dai Ito
    BACKGROUND/AIMS: A new classification of achalasia using high-resolution manometry (HRM) has recently been suggested. Pneumatic dilatation (PD) is a common treatment for primary achalasia. The usefulness of the new classification and HRM for the treatment and follow-up of patients after PD is unknown. The aim of this study was to evaluate the PD effectiveness and the predictive factors of success in Japanese patients with achalasia using HRM and the new classification of achalasia. METHODS: Twenty-five patients were diagnosed with primary achalasia using HRM and treated by PD in our hospital. We evaluated symptom scores and esophageal manometry 6 and 12 months after the first PD. RESULTS: After the first PD treatment, remission occurred in 24 out of 25 (96.0%) patients at 6 months and in 19 out of 25 (76.0%) patients at 12 months. With the new classification of achalasia, the success rates were 83.3, 80.0 and 50% for types I, II and III, respectively, 12 months after PD. The median age of the successful group was significantly greater than that of the failure group (47.1 vs. 37.0 years, p < 0.05). The median residual lower esophageal sphincter (LES) pressure 6 months after PD in the successful group was significantly lower than that of the failure group (9.0 vs. 15.5 mm Hg, p < 0.05). CONCLUSION: Good predictors of PD success were old age (>40 years) and residual LES pressures less than 15 mm Hg 6 months after PD.
    S. Karger {AG}, 2013年, Digestion, 87(1) (1), 23 - 28, 英語, 国際誌
    研究論文（学術雑誌）

  • Hiroshi Yamashita, Kiyoshi Ashida, Takumi Fukuchi, Yoshiaki Nagatani, Hideaki Koga, Kasane Senda, Takaaki Eguchi, Satoshi Ubukata, Shinpei Kawaguchi, Aya Ueda, Toshio Tanaka, Rina Ohashi, Dai Ito
    BACKGROUND: Data on acid and non-acid reflux patterns and esophageal function in Japanese patients with non-erosive reflux disease (NERD) are limited. The aim of this study was to use combined multichannel intraluminal impedance pH monitoring (MII-pH) and high-resolution manometry (HRM) to investigate the characteristics of Japanese patients who were treated with a "double-dose" (20 mg) of rabeprazol (a proton-pump inhibitor; PPI) for persistent symptoms of NERD. METHODS: Twenty-five patients who complained of typical gastroesophageal reflux disease symptoms, which had occurred more than twice a week despite treatment with rabeprazol, were enrolled in the study. All patients underwent upper endoscopy, esophageal HRM, and 24-h MII-pH monitoring while double-dose PPI therapy was continued. RESULTS: Twelve (48.0%) of the patients had a positive symptom index (SI) with 234 recorded symptoms, 127 (54.3%) of which were related to reflux episodes. Of those with reflux episodes, 29 (22.8%) were related to acid reflux, while 98 (77.2%) were the result of a weaker acidic reflux. In acid reflux and in mixed (liquid-gas) reflux, the proximal esophageal region was involved to a significantly greater degree (P<0.002 and P=0.005, respectively) than the distal region. In liquid reflux, there was no difference between the distal and proximal regions. HRM showed that proximal motility parameters were significantly more defective than in those of healthy volunteers. CONCLUSIONS: MII-pH monitoring indicated that weakly acidic reflux and mixed refluxate in the proximal esophagus is the major cause of persistent symptoms in patients with NERD who are being treated with PPI. HRM showed that proximal esophageal dysfunction might be a key condition that facilitates reflux.
    Japan Society of Smooth Muscle Research, 2012年, Journal of Smooth Muscle Research, 48(5{\_}6) (5{\_}6), 125 - 135, 英語, 国内誌
    研究論文（学術雑誌）

■ MISC
  • Remarkable response to cetuximab-containing chemotherapy for tongue cancer refractory to immune checkpoint inhibitors
    Hirotaka Suto, Naomi Kiyota, Yoshinori Imamura, Yasuko Hyogo, Kei Takenaka, Yoshiaki Nagatani, Meiko Nishimura, Masanori Toyoda, Toru Mukohara, Hironobu Minami
    2017年10月, ANNALS OF ONCOLOGY, 28, 英語
    研究発表ペーパー・要旨（国際会議）

■ 書籍等出版物
■ 講演・口頭発表等
  • Trop-2 and Nectin-4 expression and their relationship with tumor immune microenvironment in salivary gland cancer
    Yoshiaki Nagatani, Naomi Kiyota, Yoshinori Imamura, Taiji Koyama, Shiro Kimbara, Yohei Funakoshi, Tomoo Itoh, Hajime Fujiwara, Hikari Shimoda, Masanori Teshima, Ken-Ichi Nibu, Kazuko Sakai, Kazuto Nishio, Daiki Ikarashi, Shigehisa Kitano, Hironobu Minami
    ESMO Asia 2024, 2024年12月
    ポスター発表

  • 進行・再発・転移の固形腫瘍における血栓塞栓症と出血リスク PROVE-emboli試験post-hoc解析
    今村 善宣, 能勢 拓, 大幡 真也, 乙井 一典, 森 健太, 辻 高寛, 宮田 吉晴, 金原 史朗, 長谷 善明, 小山 泰司, 船越 洋平, 清田 尚臣, 南 博信
    日本血栓止血学会, 2024年05月, 日本語

  • プラチナ製剤および抗PD-1抗体薬既治療頭頸部がんに対するパクリタキセル+隔週セツキシマブの第2相試験
    朴 将源, 小山 泰司, 今村 善宣, 田中 薫, 尾上 琢磨, 浅田 行紀, 山崎 知子, 長谷 善明, 手島 直則, 四宮 弘隆, 清田 尚臣
    日本頭頸部癌学会, 2024年05月, 日本語

  • びまん性胃癌における遺伝子変異と腫瘍免疫微小環境から考える複合免疫療法
    長谷善明, 船越洋平, 南博信
    第110回 消化器病学会総会, 2024年05月
    [招待有り]
    シンポジウム・ワークショップパネル（指名）

  • A phase II trial of paclitaxel plus biweekly cetuximab for patients with recurrent or metastatic head and neck cancer previously treated with both platinum-based chemotherapy and anti-PD-1 antibody.
    Koyama T, Kiyota N, Imamura Y, Boku S, Shibata N, Satake H, Tanaka K, Hayashi H, Iwae S, Onoe T, Asada Y, Yamazaki T, Nose T, Ohata S, Kimbara S, Nagatani Y, Minami H.
    ASCO Annual Meeting 2023, 2023年06月

  • A phase II trial of nivolumab for patients with platinum-refractory recurrent or metastatic salivary gland cancer
    Yoshiaki Nagatani, Naomi Kiyota, Tomoko Yamazaki, Yukinori Asada, Masaaki Higashino, Masahiro Goto, Hironaga Satake, Ichiro Ota, Hirokazu Uemura, Katsunari Yane, Kaoru Tanaka, Takuma Onoe, Shigemichi Iwae, Shigeru Hirano, Yoshinori, Imamura, Shiro Kimbara, Taku Nose, Taiji Koyama, Yohei Funakoshi, Hironobu Minami
    ASCO Annual Meeting 2023, 2023年06月
    ポスター発表

  • 進行・再発・転移の未治療固形がん患者における静脈血栓塞栓症の前向き観察研究の統合解析
    今村 善宣, 能勢 拓, 大幡 真也, 森 健太, 乙井 一典, 宮田 吉晴, 金原 史朗, 長谷 善明, 小山 泰司, 船越 洋平, 清田 尚臣, 南 博信
    日本血栓止血学会, 2023年05月, 日本語

  • 当院における甲状腺がんに対するがん遺伝子パネル検査の現状と課題
    小山 泰司, 清田 尚臣, 今村 善宣, 長谷 善明, 下田 光, 手島 直則, 四宮 弘隆, 宮脇 大輔, 佐々木 良平, 丹生 健一
    日本頭頸部癌学会, 2023年05月, 日本語

  • 進行頭頸部扁平上皮がん患者における静脈血栓塞栓症 前向き観察研究サブ解析
    今村 善宣, 小山 泰司, 長谷 善明, 手島 直則, 四宮 弘隆, 宮脇 大輔, 佐々木 良平, 丹生 健一, 清田 尚臣
    日本頭頸部癌学会, 2023年05月, 日本語

  • Tumor Immune Microenvironment in Salivary Gland Cancer
    Yoshiaki Nagatani, Naomi Kiyota, Yoshinori Imamura, Taiji Koyama, Yohei Funakoshi, Masato Komatsu, Masanori Teshima, Ken-Ichi Nibu, Kazuko Sakai, Kazuto Nishio, Manami Shimomura, Tetsuya Nakatsura, Daiki Ikarashi, Takayuki Nakayama, Shigehisa Kitano, Hironobu Minami
    JSMO 2023, 2023年03月
    ポスター発表

  • がん関連静脈血栓塞栓症に対するアピキサバン療法の出血リスク予測 多施設共同第2相臨床試験副次的解析
    今村 善宣, 能勢 拓, 宮田 吉晴, 小山 泰司, 長谷 善明, 金原 史朗, 船越 洋平, 清田 尚臣, 藥師神 公和, 南 博信
    日本内科学会, 2023年02月, 日本語

  • Tumor Immune Microenvironment in Salivary Gland Cancer
    Yoshiaki Nagatani, Naomi Kiyota, Yoshinori Imamura, Taiji Koyama, Yohei Funakoshi, Masato Komatsu, Masanori Teshima, Ken-Ichi Nibu, Kazuko Sakai, Kazuto Nishio, Manami Shimomura, Tetsuya Nakatsura, Daiki Ikarashi, Takayuki Nakayama, Shigehisa Kitano, Hironobu Minami
    AACR 2022, 2022年04月
    ポスター発表

  • 再発・転移頭頸部扁平上皮癌に対するニボルマブ療法治療の予後予測における好酸球数変化の有用性
    小山 泰司, 清田 尚臣, 今村 善宣, 長谷 善明, 蓼原 瞬, 手島 直則, 四宮 弘隆, 宮脇 大輔, 佐々木 良平, 丹生 健一
    日本頭頸部癌学会, 2021年05月, 日本語

  • Immunosuppressive effects and mechanisms of three Myeloid-derived suppressor cell (MDSC) subsets including M-MDSC, G-MDSC, and I-MDSC
    Yoshiaki Nagatani, Yohei Funakoshi, Hirotaka Suto, Yoshinori Imamura, Masanori Toyoda, Naomi Kiyota, Kimihiro Yamashita, Hironobu Minami
    JSMO 2021, 2021年02月
    口頭発表（一般）

  • 頭頸部癌における免疫チェックポイント阻害薬後の救済化学療法についての後方視的検討
    小山 泰司, 清田 尚臣, 今村 善宣, 長谷 善明, 高倉 嗣丈, 蓼原 瞬, 入谷 啓介, 古川 竜也, 手島 直則, 四宮 弘隆, 宮脇 大輔, 明石 昌也, 佐々木 良平, 丹生 健一
    日本頭頸部癌学会, 2020年07月, 日本語

  • 当院における頭頸部がんに対する高用量シスプラチン併用化学放射線療法による急性腎障害の後方視的検討
    高倉 嗣丈, 今村 善宣, 小山 泰司, 長谷 善明, 四宮 弘隆, 手島 直則, 古川 竜也, 入谷 啓介, 蓼原 瞬, 宮脇 大輔, 明石 昌也, 佐々木 良平, 丹生 健一, 清田 尚臣
    日本頭頸部癌学会, 2020年07月, 日本語

  • がん免疫療法時代の再発・転移頭頸部扁平上皮癌における全身性炎症スコアの予後予測性
    今村 善宣, 清田 尚臣, 小山 泰司, 金原 史朗, 長谷 善明, 須藤 洋崇, 能勢 拓, 船越 洋平, 豊田 昌徳, 南 博信
    日本内科学会, 2020年02月, 日本語

  • 3. Relationship between tumor burden to growth rate and treatment outcomes of nivolumab for patients with head and neck squamous carcinoma
    Suzuki C., Kiyota N., Imamura Y., Rikitake J., Sai S., Koyama T., Hyogo Y., Nagatani Y., Funakoshi Y., Toyoda M., Otsuki N., Nibu K., Minami H.
    ASCO-SITC 2019, 2019年02月

  • 2. A Phase II Trial of Docetaxel plus Cisplatin in Recurrent and/or Metastatic Non-squamous Cell Carcinoma of Head and Neck
    Imamura Y., kiyota N., Tanaka K., Hayashi H., Ota I., Nario K., Hirano S., Arai A., Iwae S., Onoe T., Minami S., Shimada T., Yane K., Yamazaki T., Nagatani Y., Toyoda M., Otsuki N., Nibu K., Minami H.
    ESMO congress 2018, 2018年09月

  • Pharmacokinetics of oxaliplatin in a hemodialysis patient with metastatic colon cancer
    Yoshiaki Nagatani, Yoshinori Imamura, Tsutomu Nakamura, Kazuhiko Yamashita, Mamoru Okuno, Hiroyuki Yasui, Jun Hiraoka, Riho Niigata, Yasuko Hyogo, Hirotaka Suto, Kei Takenaka, Yohei Funakoshi, Masanori Toyoda, Naomi Kiyota, Hironobu Minami
    JSMO 2018, 2018年07月
    ポスター発表

  • 再発・転移の頭頸部非扁平上皮癌に対するドセタキセル+シスプラチン併用療法の第II相臨床試録
    今村 善宣, 清田 尚臣, 田中 薫, 林 秀俊, 太田 一郎, 平野 滋, 岩江 信法, 南 修司郎, 家根 且有, 山崎 知子, 長谷 善明, 豊田 昌徳, 大月 直樹, 丹生 健一, 南 博信
    日本頭頸部癌学会, 2018年05月, 日本語

  • 次世代シークエンサーを用いた唾液腺導管癌・腺癌NOSの新規治療標的遺伝子の同定
    今村 善宣, 清田 尚臣, 長谷 善明, 鈴木 千晶, 兵庫 寧子, 崔 諭司, 力武 隼平, 船越 洋平, 豊田 昌徳, 南 博信
    日本内科学会, 2018年02月, 日本語

  • Safety and efficacy of induction chemotherapy with TPF for locally advanced head and neck squamous cell carcinoma
    Yoshiaki Nagatani, Naomi Kiyota, Yoshinori Imamura, Kei Takenaka, Hirotaka Suto, Yasuko Hyogo, Meiko Nishimura, Masanori Toyoda, Toru Mukohara, Hironobu Minami
    JSMO 2017, 2017年07月
    ポスター発表

  • 局所進行頭頸部扁平上皮癌における導入化学療法TPFの安全性と有効性の検討
    長谷 善明, 清田 尚臣, 今村 善宜, 宮脇 大輔, 佐々木 良平, 四宮 弘隆, 大月 直樹, 丹生 健一
    日本頭頸部癌学会, 2017年05月, 日本語

  • Clinical outcomes of patients with gastrointestinal stromal tumor in phase I clinical trials
    Nagatani Y., Shitara K., Bando H., Kuboki Y., Okamoto W., Kojima T., Yoshino T., Nishida T., Ohtsu A., Doi T.
    ESMO congress 2015, 2015年09月
    ポスター発表

  • Clinical outcomes of patients with gastrointestinal stromal tumor in phase I clinical trials
    Nagatani Y., Shitara K., Bando H., Kuboki Y., Okamoto W., Kojima T., Yoshino T., Nishida T., Ohtsu A., Doi T.
    JSMO 2015, 2015年07月
    口頭発表（一般）

  • Symptom indexはPPI抵抗性NERDの病態を反映する
    長谷 善明, 山下 博司, 岩坪 太郎, 黒澤 学, 安富 栄一郎, 川口 真平, 古賀 英彬, 生方 聡史, 江口 考明, 田中 敏雄, 福知 工, 伊藤 大, 蘆田 潔
    日本消化器病学会, 2013年09月, 日本語

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